Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

K. Nho, J. J. Corneveaux, S. Kim, H. Lin, S. L. Risacher, L. Shen, S. Swaminathan, V. K. Ramanan, Y. Liu, T. Foroud, M. H. Inlow, A. L. Siniard, R. A. Reiman, P. S. Aisen, R. C. Petersen, R. C. Green, C. R. Jack, M. W. Weiner, C. T. Baldwin, K. LunettaL. A. Farrer, S. J. Furney, S. Lovestone, A. Simmons, P. Mecocci, B. Vellas, M. Tsolaki, I. Kloszewska, H. Soininen, B. C. McDonald, M. R. Farlow, B. Ghetti, M. J. Huentelman, A. J. Saykin

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)781-787
Number of pages7
JournalMolecular Psychiatry
Volume18
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • ADNI
  • CARD10
  • imaging genetics
  • mild cognitive impairment
  • PARP1
  • whole-exome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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